title: Pharmacokinetics, pharmacodynamics and safety of a human anti-IL-6 monoclonal antibody (sirukumab) in healthy subjects in a first-in-human study.
abstract: BACKGROUND
  Interleukin (IL)-6 is a cytokine known for pleiotropic and pro-inflammatory functions. IL-6 is involved in various disease processes including lupus erythematosus, rheumatoid arthritis, insulin resistance and malignancy. Anti-IL-6 receptor therapy has recently been demonstrated to be effective in the treatment of patients with rheumatoid arthritis.
  
  
  CONCLUSIONS
  Sirukumab, a human monoclonal antibody against soluble IL-6, has been found to bind to human IL-6 with high affinity and specificity and thus suppress the biological activity of IL-6. Preclinical studies have demonstrated the safety of sirukumab in cynomolgus monkeys, a toxicologically relevant animal species, following repeated intravenous and subcutaneous administrations. This study shows that sirukumab has desirable pharmacokinetic characteristics (linear pharmacokinetics with long half-life), a low incidence of immunogenicity and a well-tolerated safety profile in healthy subjects, supporting further development of sirukumab as a potentially valuable therapeutic agent.
  
  
  OBJECTIVE
  To assess the safety, tolerability, pharmacokinetics (PK) and immunogenicity of sirukumab (CNTO 136) following intravenous (i.v.) infusion in healthy subjects.
  
  
  METHODS
  Forty-five healthy adult subjects (38 men and seven women) were randomly assigned to receive a single i.v. dose of placebo or sirukumab (0.3, 1, 3, 6 or 10 mg kg(-1) in a dose-escalating manner). All treated subjects were observed for 96 h post infusion and underwent 20-week follow-up evaluations. Serum samples were collected to measure sirukumab concentrations, pharmacodynamic biomarkers and antibodies to sirukumab. Non-compartmental analysis and population PK modelling were conducted to characterize the PK of sirukumab.
  
  
  RESULTS
  Adverse events were generally brief in duration, mild or moderate in intensity and non-dose-dependent. No serious adverse events were observed in the sirukumab-treated subjects. Both C(max) and AUC(0,∞) increased in an approximately dose-proportional manner. Median terminal half-life ranged from 18.5 to 29.6 days. A two-compartment model adequately described the PK of sirukumab following i.v. administration. Population estimates for the clearance (CL), the central volume of distribution (V(1)), the inter-compartmental clearance (Q) and the peripheral volume of distribution (V(2)) were 0.364 l day(-1), 3.28 l, 0.588 l day(-1) and 4.97 l, respectively. Compared with placebo subjects, a sustained decrease from baseline in C-reactive protein was observed in all sirukumab-treated dose groups, although no clear dose-response relationship was observed. No subjects were positive for antibodies to sirukumab.
  
  
  CONCLUSIONS
  Sirukumab had a well-tolerated safety profile, desirable PK characteristics and a low incidence of immunogenicity following an i.v. infusion of 0.3 to 10 mg kg(-1) in healthy subjects.
authors.affiliation: Centocor Research & Development, Inc., 200 Great Valley Parkway, Malvern, PA 19355, USA.
authors.forename: Zhenhua
authors.initials: Z
authors.lastname: Xu
authors.forename: Esther
authors.initials: E
authors.lastname: Bouman-Thio
authors.forename: Craig
authors.initials: C
authors.lastname: Comisar
authors.forename: Bart
authors.initials: B
authors.lastname: Frederick
authors.forename: Bart
authors.initials: B
authors.lastname: Van Hartingsveldt
authors.forename: Joseph C
authors.initials: JC
authors.lastname: Marini
authors.forename: Hugh M
authors.initials: HM
authors.lastname: Davis
authors.forename: Honghui
authors.initials: H
authors.lastname: Zhou
mesh_terms: D000293:Adolescent; D000328:Adult; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized; D019540:Area Under Curve; D004311:Double-Blind Method; D005260:Female; D006207:Half-Life; D006801:Humans; D007262:Infusions, Intravenous; D015850:Interleukin-6 / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D055815:Young Adult
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D015850:Interleukin-6; C568922:sirukumab; C504234:siltuximab